First medical product cleared in U.S. for use on certain injuries caused by sulfur mustard

The U.S. government reached a milestone in its long-standing efforts to defend the country against potential use of chemical weapons: the first U.S. Food and Drug Administration (FDA) clearance of a product to manage certain blister injuries caused by sulfur mustard, commonly known as mustard gas.

“Our top priority is saving lives during national emergencies. To do so, we must make safe and effective medical products for all the illnesses and injuries stemming from the serious health security threats confronting our nation,” said Robert Kadlec, M.D., Assistant Secretary for Preparedness and Response (ASPR) at U.S. Department of Health and Human Services. “This product clearance is the latest step in delivering on that promise to the American people.”

The ASPR’s Biomedical Advanced Research and Development Authority (BARDA) provided technical expertise and funding to support the studies necessary to show that the product, Silverlon, is appropriate for use on first- and second-degree skin burns caused by exposure to sulfur mustard.

“Chemical weapons like sulfur mustard cause horrific, painful, and life-altering injuries, yet in the 100-year history of sulfur mustard use, no medical countermeasures existed – until now,” added BARDA Director Rick Bright, Ph.D. “At BARDA, we are excited to have supported the first cleared product for use on skin injuries caused by sulfur mustard. This clearance exemplifies BARDA’s ongoing commitment to our partners and the nation as we seek out promising technologies and products to improve our nation’s health security and protect Americans.”

Argentum Medical, LLC, has received FDA clearances for multiple indications for Silverlon since 2003 and in that time the wound dressing has been used extensively by the U.S. military to treat burn and blast wounds. Silverlon dressings also are used widely by the healthcare and first responder communities.

“The FDA plays an important role in preparing our nation for a range of threats, including chemical, biological, radiological, and nuclear threats, providing guidance and support for the development of medical countermeasures that can be used safely, effectively and reliably during public health emergencies,” said Acting FDA Commissioner Ned Sharpless, M.D. “The expanded indication for this first-of-its-kind wound contact dressing to include management of certain injuries caused by sulfur mustard vapor exposure demonstrates our commitment to working closely with our federal partners, including BARDA, to expedite the availability of medical countermeasures essential for managing responses to chemical weapons attacks in both civilian and battlefield settings.”

BARDA’s support for this additional indication began in 2013 as part of the federal government’s effort to repurpose approved drugs and medical products to save lives and reduce injury in an attack on the United States.

This multi-purpose approach has proven to be cost-effective in preparing mass casualty emergencies from chemical, biological, and radiological agents. Repurposing products in widespread use additionally ensures first responders have a familiar product to use in a time of crisis.

Beginning in 2015, BARDA used Project BioShield authorities and the Project BioShield Special Reserve Fund to purchase Silverlon for the Strategy National Stockpile as part of BARDA’s burn countermeasure program. BARDA continues to work with Argentum on studies necessary for FDA clearance of Silverlon for use on radiation burns.

Silverlon is a silver-plated nylon dressing available commercially and used widely to aid in the management of acute skin wounds and first- and second-degree thermal burns. The silver plating helps kill bacteria within the dressing, and one dressing can be used for up to seven days. This allows for fewer dressing changes, which reduces the burden on caregivers and minimizes the pain and damage that would occur if the wound was disturbed.

Sulfur mustard was first used as a chemical weapon in World War I and can be released into the air, food or water. More recently the chemical was used in the Iran-Iraq war and in the Syrian Civil War.

After the incidents in the United Kingdom (U.K.) in 2018 involving a fourth generation agent, the White House National Security Council convened a federal interagency working group to identify and develop resources to help the emergency response community prepare for and respond to a fourth generation agent incident if one ever occurs in the U.S., as well as support the development of specific guidance and training to enhance overall preparedness efforts. These resources meet the needs of U.S. emergency response professionals who sought to learn more about the agent used in the U.K. and how to protect themselves and respond if such incidents ever occur in their communities.

Fourth generation agents, also known as Novichoks or A-series nerve agents, belong to a category of chemical warfare agents that are unique organophosphorus compounds. They are more persistent than other nerve agents and are at least as toxic as VX. While fourth generation agents share similar characteristics with other nerve agents, fourth generation agents also pose several unique challenges in terms of toxicity, detection, persistence, and potential for delayed onset of symptoms. The following resources were developed to address these characteristics and challenges and provide tailored guidance to various segments of the emergency response community.

Safety Awareness for First On-Scene Responders Bulletin – Designed to educate and prepare first responders for situations when law enforcement, fire, and emergency medical services (EMS) personnel are first to arrive on scene and initially may be unaware that a fourth generation agent is present. This bulletin will assist departments and agencies develop specific guidance and training to enhance overall preparedness efforts. (PDF – 791 KB)

Reference Guide – Designed to educate and prepare hazardous materials (HAZMAT) response teams, the guide includes chemical and physical properties of fourth generation agents, as well as detection, firefighting, personal protective equipment, and decontamination recommendations for situations when responding to a known or suspected fourth generation agent incident. This guide will assist HAZMAT response teams develop specific guidance and training to enhance overall preparedness efforts. (PDF – 789 KB)

Medical Management Guidelines – Designed to educate and prepare fire, EMS, and hospital staff and guide the medical management of patients exposed or potentially exposed to a fourth generation agent. (PDF – 858 KB) (Note: This is one PDF document that is divided into two Web pages, one for pre-hospital care and one for in-hospital care.)

These resources were developed by a federal interagency working group comprising experts in medicine, science, public health, law enforcement, fire, EMS, HAZMAT, and occupational safety and health from the Department of Defense, Department of Health and Human Services (Office of the Assistant Secretary for Preparedness and Response, Centers for Disease Control and Prevention, and National Institute for Occupational Safety and Health), Department of Transportation (Pipeline and Hazardous Materials Safety Administration and National Highway Traffic Safety Administration’s Office of Emergency Medical Services), Department of Homeland Security, Federal Bureau of Investigation, Occupational Safety and Health Administration, and Environmental Protection Agency.

These resources are based on the interpretation of available data on fourth generation agents by U.S. government experts and previously developed federal guidance related to nerve agents. Moreover, the guidance was developed through a collaborative process which included extensive stakeholder review in the form of listening sessions and consultations with representatives from the various disciplines across the emergency response community.

Information as of January 18, 2019, was used to inform the development of these resources. They will be updated as new data becomes available that can further support any response to a potential fourth generation agent incident and help protect responders if such an incident ever occurs in the U.S.

Please refer comments and questions on these fourth generation agent resources to askasprtracie@hhs.gov.

Description of chart:

Issuance of an EUA by the FDA Commissioner requires several steps under section 564 of the FD&C Act. First, one of the four following determinations must be in place:

The Department of Defense (DoD) Secretary issues a determination of military emergency or significant potential for military emergency

The Department of Homeland Security (DHS) Secretary issues a determination of domestic emergency or significant potential for domestic emergency.

The Department of Health and Human Services (HHS) Secretary issues a determination of public health emergency or significant potential for public health emergency

The DHS Secretary issues a material threat determination

After one of the above four determinations is in place, the HHS Secretary can issue a declaration that circumstances exist to justify issuing the EUA. This declaration is specific to EUAs and is not linked to other types of emergency declarations.

The FDA Commissioner, in consultation with the HHS Assistant Secretary for Preparedness and Response (ASPR), Centers for Disease Control and Prevention (CDC), and the National Institutes of Health (NIH), can then issue the EUA, if criteria for issuance under the statute are met. FDA publishes public notice of each EUA that is issued in the Federal Register.

The last step in the process is termination of declaration and EUA, if appropriate and needed.

“……Investigators released a cache of evidence in the case, including security camera images that captured the progress of two husky men [Alexander Petrov and Ruslan Boshirov] from an Aeroflot flight to the scene of the crime, near the victim’s home, and from there back to Moscow.

Some witnesses described a “slow-acting agent” that smelled like chlorine, the draft said, and they had sufficient time “to rouse the victims, obtain wet cloths to serve as makeshift face masks, and evacuate the affected areas.”……..Thirty-one people, including 11 children, were sickened in the first three attacks, but none died. Two other episodes of possible chlorine use, on Feb. 25 and March 7, caused more extensive casualties, killing two children, including an infant, and injuring 18 civilians...…..”

“…..Dr Stephen Jukes, an intensive care consultant at the hospital, said: “When we first were aware this was a nerve agent, we were expecting them not to survive.

“We would try all our therapies. We would ensure the best clinical care. But all the evidence was there that they would not survive.”

Both Skripals were heavily sedated which allowed them to tolerate the intrusive medical equipment they were connected to, but also helped to protect them from brain damage, a possible consequence of nerve agent poisoning.

Over time, the sedation was reduced and the ventilation switched from the mouth to the trachea, as shown by the vivid scar seen on Yulia Skripal’s neck in the TV statement she gave after she was released.

Once the patients became more conscious, staff had to carefully consider what they could tell them without prejudicing the police investigation, and decide on the right moment to allow questioning by detectives.

Medical director Dr Christine Blanshard explained: “Those are very difficult decisions, because on the one hand you want to provide reassurance to the patients that they are safe and they are being looked after, and on the other hand you don’t want to give them information that might cause difficulties with subsequent police interviews.”

It was the doctors and nurses that, out of concern for their patients, insisted that international inspectors obtain a court order before they would be allowed to take blood samples from the Skripals.

Dr Jukes explained: “These are vulnerable patients, they needed some form of advocate and without a court order we could not allow things to happen to them without their consent.”

Once the Skripals were stable and able to speak, the key concern for medical staff was how their production of the key enzyme acetylcholinesterase – needed to re-establish their normal body functions – could be stimulated.

The body will do this naturally after nerve agent poisoning, but the process can take many months.

In trying combinations of drugs, Dr Murray says the hospital received input from “international experts”, some of them from Porton Down.

The laboratory, internationally known for its chemical weapons expertise, processed tests and offered advice on the best therapies.

New approaches to well-known treatments were tried. Dr Jukes said that the speed of the Skripals’ recovery came as a very pleasant surprise that he cannot entirely explain……”

‘……….“One thing, perhaps, which is important to note is that the nerve agent seems to be very persistent,” he said. “It’s not affected by weather conditions. That explains, actually, that they were able to identify it after a considerable time lapse. We understand it was also of high purity.”

He said the agent could be applied with an aerosol spray or, “if you take the necessary measures, you could use it as a liquid.”

Health officials have begun a meticulous decontamination process, warning citizens of Salisbury that there might still be toxic “hot spots” in some areas, and that a thorough cleanup may take months.

Though citizens have been reassured that there is little threat to their health, the decontamination promises to be a vast undertaking, requiring backup from 190 army and air force specialists as well as input from the Defense Science and Technology Laboratory, the Home Office and the Ministry of Defense…..’

James Lawler is “…a retired Navy commander whose experience includes serving as director for medical preparedness policy on the National Security Council and director for biodefense policy on the White House’s Homeland Security Council…”

“….Kenneth Luongo, president and founder of the Partnership for Global Security, echoed that the U.S. “remains woefully underprepared” for a biological attack or a “new intensity level” of pathogens…..”

“….Former USAID Director Andrew Natsios, director of the Scowcroft Institute of International Affairs, told the panel that the country is “a lot more fragile than we realize” when it comes to emergency response….”

This document is based on technical analyses of open source information and declassified intelligence obtained by French services.
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I. SEVERAL LETHAL CHEMICAL ATTACKS TOOK PLACE IN THE TOWN OF DOUMA IN THE LATE AFTERNOON OF SATURDAY, 7 APRIL 2018, AND WE ASSESS WITH A HIGH DEGREE OF CONFIDENCE THAT THEY WERE CARRIED OUT BY THE SYRIAN REGIME.

Following the Syrian regime’s resumption of its military offensive, as well as high levels of air force activity over the town of Douma in Eastern Ghouta, two new cases of toxic agents employment were spontaneously reported by civil society and local and international media from the late afternoon of 7 April. Non-governmental medical organizations active in Ghouta (the Syrian American Medical Society and the Union of Medical Care and Relief Organizations), whose information is generally reliable, publicly stated that strikes had targeted in particular local medical infrastructure on 6 and 7 April.

A massive influx of patients in health centres in Eastern Ghouta (at the very least 100 people) presenting symptoms consistent with exposure to a chemical agent was observed and documented during the early evening. In total, several dozens of people, more than forty according to several sources, are thought to have died from exposure to a chemical substance.

The information collected by France forms a body of evidence that is sufficient to attribute responsibility for the chemical attacks of 7 April to the Syrian regime.

1. – Several chemical attacks took place at Douma on 7 April 2018.

The French services analysed the testimonies, photos and videos that spontaneously appeared on specialized websites, in the press and on social media in the hours and days following the attack. Testimonies obtained by the French services were also analysed. After examining the videos and images of victims published online, they were able to conclude with a high degree of confidence that the vast majority are recent and not fabricated. The spontaneous circulation of these images across all social networks confirms that they were not video montages or recycled images. Lastly, some of the entities that published this information are generally considered reliable.

French experts analysed the symptoms identifiable in the images and videos that were made public. These images and videos were taken either in enclosed areas in a building where around 15 people died, or in local hospitals that received contaminated patients. These symptoms can be described as follows (cf. annexed images):

No deaths from mechanical injuries were visible. All of these symptoms are characteristic of a chemical weapons attack, particularly choking agents and organophosphorus agents or hydrocyanic acid. Furthermore, the apparent use of bronchodilators by the medical services observed in videos reinforces the hypothesis of intoxication by choking agents.

2. – Given in particular ongoing military operations in Eastern Ghouta around 7 April, we assess with a high degree of confidence that the Syrian regime holds responsibility.

Reliable intelligence indicates that Syrian military officials have coordinated what appears to be the use of chemical weapons containing chlorine on Douma, on April 7.

The attack of 7 April 2018 took place as part of a wider military offensive carried out by the regime on the Eastern Ghouta region. Launched in February 2018, this offensive has now enabled Damascus to regain control of the entire enclave.

As a reminder, the Russian military forces active in Syria enable the regime to enjoy unquestionable air superiority, giving it the total military freedom of action it needs for its indiscriminate offensives on urban areas.

The tactic adopted by pro-regime forces involved separating the various groups (Ahrar al-Sham, Faylaq al-Rahman, and Jaysh al-Islam) in order to focus their efforts and obtain negotiated surrender agreements. The three main armed groups therefore began separate negotiations with the regime and Russia. The first two groups (Ahrar al-Sham and Faylaq al-Rahman) concluded agreements that resulted in the evacuation of nearly 15,000 fighters and their families. During this first phase, the Syrian regime’s political and military strategy consisted in alternating indiscriminate military offensives against local populations, which sometimes included the use of chlorine, and pauses in operations for negotiations.

Negotiations with Jaysh al-Islam began in March but were not fully conclusive. On 4 April, part of the Jaysh al-Islam group (around one quarter of the group according to estimates) accepted the surrender agreement and fighters and their families were sent to Idlib (approximately 4,000 people, with families). However, between 4,500 and 5,500 Jaysh al-Islam fighters, mostly located in Douma, refused the terms of negotiation. As a result, from 6 April onwards, the Syrian regime, with support from Russian forces, resumed its intensive bombing of the area, ending a pause in ground and aerial operations that had been observed since negotiations began in mid-March. This was the context for the chemical strikes analysed in this document.

Given this context, the Syrian regime’s use of chemical weapons makes sense from both the military and strategic points of view:

 Tactically speaking, this type of ammunition is used to flush out enemy fighters sheltering in homes and engage in urban combat in conditions that are more
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favourable to the regime. It accelerates victory and has a multiplier effect that helps speed up the capitulation of the last bastion of armed groups.

 Strategically speaking, chemical weapons and particularly chlorine, documented in Eastern Ghouta since early 2018, are especially used to punish civilian populations present in zones held by fighters opposed to the Syrian regime and to create a climate of terror and panic that encourages them to surrender. As the war is not over for the regime, it uses these indiscriminate strikes to show that resistance is futile and pave the way for capturing these last pockets of armed resistance.

 Since 2012, the Syrian forces have repeatedly used the same pattern of military tactics: toxic chemicals are mainly used during wider urban offensives, as was the case in late 2016 during the recapture of Aleppo, where chlorine weapons were regularly used in conjunction with traditional weapons. The zones targeted, such as Eastern Ghouta, are all major military objectives for Damascus.

3. – The French services have no information to support the theory whereby the armed groups in Ghouta would have sought to acquire or have possessed chemical weapons.

The French services also assess that a manipulation of the images circulated massively from Saturday, 7 April is not credible, in part because the groups present in Ghouta do not have the resources to carry out a communications operation on such a scale.

II. SINCE APRIL 2017, THE SYRIAN REGIME HAS USED CHEMICAL WEAPONS AND TOXIC AGENTS IN ITS MILITARY OPERATIONS INCREASINGLY OFTEN.

The French services assess that Syria did not declare all of its stockpiles and capacities to the Organisation for the Prohibition of Chemical Weapons (OPCW) during its late, half-hearted accession to the Chemical Weapons Convention (CWC) in October 2013.

Syria omitted, notably, to declare many of the activities of its Scientific Studies and Research Centre (SSRC). Only recently has it accepted to declare certain SSRC activities under the Chemical Weapons Convention (CWC), but not, however, all of them. Initially, it also failed to declare the sites at Barzeh and Jemraya, eventually doing so in 2018.

The French services assess that four questions asked of the Syrian regime by the OPCW and which have remained unanswered require particular attention, particularly in the context of these latest cases of the use of chemical weapons in Syria: – possible remaining stocks of yperite (mustard gas) and DF (a sarin precursor); – undeclared chemical weapons of small calibre which may have been used on several occasions, including during the attack on Khan Sheikhoun in April 2017;
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– signs of the presence of VX and sarin on production and loading sites; – signs of the presence of chemical agents that have never been declared, including nitrogen mustard, lewisite, soman and VX.

Since 2014, the OPCW Fact-Finding Mission (FFM) has published several reports confirming the use of chemical weapons against civilians in Syria. The UN-OPCW Joint Investigation Mechanism (JIM) on chemical weapons attacks has investigated nine occasions when they have allegedly been used. In its August and October 2016 reports, the JIM attributed three cases of the use of chlorine to the Damascus regime and one case of the use of yperite to Daesh, but none to any Syrian armed group.

5. – A series of chemical attacks has taken place in Syria since 4 April 2017

A French national assessment published on 26 April 2017 following the Khan Sheikhoun attack listed all the chemical attacks in Syria since 2012, along with the assessment of their probability according to French services. This attack, carried out in two phases, at Latamneh on 30 March, and then at Khan Sheikhoun with sarin gas on 4 April, led to the death of more than 80 civilians. The French authorities considered at the time that it was very likely that the Syrian armed and security forces held responsibility for the attack.

The French services have identified 44 allegations of the use of chemical weapons and toxic agents since 4 April 2017, the date of the sarin attack on Khan Sheikhoun. Of these 44 allegations, the French services consider that the evidence collected around 11 of the attacks gave reason to assess they were of a chemical nature. Chlorine is believed to have been used in most cases, while the services also believe a neurotoxic agent was used at Harasta on 18 November 2017.

In this context, a considerable rise in cases of use can be noted since the non-renewal of the mechanism of the UN-OPCW Joint Investigation Mechanism (JIM) in November 2017 because of Russia’s veto at the UN Security Council. A considerable increase in chlorine attacks since the beginning of the offensive on Eastern Ghouta has also been clearly observed and proven. A series of attacks preceded the major attack of 7 April 2018, as part of a wider offensive (at least 8 chlorine attacks in Douma, Shayfounia and Hamouria).

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These facts need to be considered in the light of a chemical warfare modus operandi of the Syrian regime that has been well documented since the attacks on Eastern Ghouta on 21 August 2013 and on Khan Sheikhoun on 4 April 2017. As part of a continuous increase in violence employed against civilians in enclaves refusing the regime’s authority, and in violation of its international obligations despite clear warnings from UN Security Council and OPCW members, Damascus seeks to seize a tactical military advantage locally, and above all to terrorize populations in order to break down all remaining resistance. It can be noted that, since the attacks of
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7 April 2018, the group Jaysh al-Islam has negotiated its departure from Douma with the regime and Russia, demonstrating the success of this tactic.

On the basis of this overall assessment and on the intelligence collected by our services, and in the absence to date of chemical samples analysed by our own laboratories, France therefore considers (i) that, beyond possible doubt, a chemical attack was carried out against civilians at Douma on 7 April 2018; and (ii) that there is no plausible scenario other than that of an attack by Syrian armed forces as part of a wider offensive in the Eastern Ghouta enclave. The Syrian armed and security forces are also considered to be responsible for other actions in the region as part of this same offensive in 2017 and 2018. Russia has undeniably provided active military support to the operations to seize back Ghouta. It has, moreover, provided constant political cover to the Syrian regime over the employment of chemical weapons, both at the UN Security Council and at the OPCW, despite conclusions to the contrary by the JIM.